Sympathetic-Epithelial Crosstalk Governs Regionalized CD8+ TRM Cell Immunosurveillance in the Skin

Epithelial cells, immune cells, and nerves converge at barrier tissues to collaboratively defend against pathogens and malignancies, but the mechanisms mediating their coordination remain poorly understood. Here we show that in the skin, sympathetic nerves interact with epidermal stem cells (EpiSCs) to regulate CD8+ tissue-resident memory T (TRM) cell density, thereby modulating local immunosurveillance against developing melanoma. Sympathetic nerves anchor on skin epithelium and establish synapse-like connections with EpiSCs, modulating their secretion of chemokine ligand CXCL16 via norepinephrine-ADRB2 signaling. Reduced sympathetic tone elevates CXCL16 secretion, increasing CD8+ TRM cell abundance in the skin epithelium and enhancing local cancer immunosurveillance. Conversely, heightened sympathetic activity during acute stress decreases CD8+ TRM cell number, allowing nascent cancer cells to evade elimination and propagate. Our study unveils a neuro-epithelial-immune axis that governs CD8+ TRM cell dynamics at barrier tissues, and illustrates how regional immunosurveillance can be influenced by systemic neuronal inputs and mental status.